Paget's disease causes a change in the composition and structure of the affected bones and results in their deformation. The disease appears in circumscribed areas and can affect one or a number of bones. It affects particularly frequently the bones of the sacrum, pelvis, femur, tibia, and the vault of the cranium.
In Paget's disease the dimensions of the affected bone or bones increase about 10-fold and newly formed bone possesses a faulty structure and is undermineralized (i.e., it contains an insufficient proportion of calcium and similar elements). The increased volume of the bone can destroy adjacent nerves and blood vessels, and the low mineral content of the bone frequently leads to their undergoing spontaneous fracture (i.e., a fracturing which has no evident cause). Osteosarcomas frequently have their site in a locus which is affected by Paget's disease.
In hypercalcemia, increased solubilization of calcium in bones frequently occurs in combination with a reduction in the amount of calcium secreted by the kidneys, and both these events lead to an increase of the calcium level in the blood serum of the mammal affected. The causes of this disease (hypercalcemia) have been ascribed to an increased sensitivity to vitamin D or to substances like vitamin-D which are produced in tumors (paraneoplastic syndrome). The symptoms of hypercalcemia have also been found in primary or secondary hyperparathyreoidism or in tumors (in many instances carcinomas) which secrete parathormone-like substances. Plasmacytomas or an estrogeninduced hypercalcemia are also possible.
Osteoporosis is one of the most frequent disorders resulting from faulty bone metabolism (i.e., catabolism), and is characterized by a loss of bone substance, the bone otherwise remaining unchanged in composition. The disease is observed in mammals in general. In men, loss of bone substance generally starts at the ages of 40 to 50, and in women it occurs particularly frequently after menopause. Disorders in the hormone balance are frequently assumed to be the cause. But non-hormal factors, e.g. the immobility of extremities and food or medicine-related factors cannot be excluded from the genesis of osteoporosis.
The loss of bone substance, measured as a percentage of the total calcium of the body before onset of the disease, can amount to 30%. Thinning of the cortical bones, as well as conversion of the bone to a spongy porous structure leads more frequently with increasing age to spontaneous fractures.
Up to the present, treatments of the above-mentioned bone diseases have been unsatisfactory. Attempts were made to slow down degradation or alteration of the bones by administration of corticoids and salicylates, but it was found that effective doses of these medicaments led rapidly to undesired side effects. Indomethacin, phenylbutazone and substances which stimulate the circulation provided temporary relief to the patient, but they had no effect on the progress of the disease. Treatments with sodium fluoride produced visible results only in a few cases.
In the last few years two new therapies were found which provided better results, particularly in Paget's disease. The hormone calcitonin, (also termed "thyrocalcitonin") which is responsible in the organism of mammals (including humans), together with Parathormone (i.e., the parathyroid hormone) for calcium homeostasis and which is formed in the parafollicular cells of the thyroid gland was found to have a definite efficacy. Calcitonin itself is a polypeptide hormone composed of 32 amino acid units. This material, as well as several animal analogs (of salmon, pig and cattle), and their synthetic analogs (hereinafter termed "calcitonins") possess the property of decreasing the level of ionic calcium (Ca.sup.2+) in the blood serum rapidly; they also possess the property of causing dissolved calcium to be absorbed or to be reabsorbed by the bone. Prolonged treatment with human calcitonin, and particularly with its synthetic and animal produced analogs, presents the danger of causing undesirable formation of antibodies and a resulting incompatibility. In addition, therapy with calcitonin does not result in a complete regression of the principal symptoms of Paget's disease, e.g. the increase in the alkaline phosphatase level in the blood serum and the increase in the secretion of hydroxyproline in the urine.
Another therapy of the above-described disorders of bone metabolism in man and other mammals is based on the administration of certain water-soluble diphosphonic compounds and other acidic compounds. These substances act primarily on the mineral phase of the bone and decrease the crystallization of apatite and the solubility of the bone materials. In addition, they appear to provide sites for absorption of the soluble calcium ions in the blood. The latter effect is based on a strong chemisorption of these compounds on the surface of calciferous minerals like apatite. These compounds contain at least two acidic substituents (e.g. phosphono, carboxy and sulfo) separated by not more than two carbon atoms, and come from the group consisting of the water-soluble aminophosphonic acids, the water-soluble amidophosphonic acids, the water-soluble carboxyphosphonic acids, cyclohexanehexacarboxylic acid, and the water-soluble salts thereof.
The increased rate of degenerative bone metabolism can be decreased by oral administration of these acidic inhibitors. Good results are obtained particularly in controlling Paget's disease. Hypercalcemia is also decreased, and osteoporosis of the bones undergoes reversal.
Though these compounds are more effective than calcitonin, prolonged therapy therewith has been found to provide undesired side effects. Not only is the rate of dissolution of the bone minerals decreased, but mineralization of the bones is inhibited, the number of unmineralized osteoplasts increases, and an increase in the number of osteo disorders occurs when large doses are administered.